Human polymorphonuclear leukocytes (PMNs) are the primary innate host defense against invading bacterial pathogens. Following phagocytosis by neutrophils, bacteria are killed by reactive oxygen species and microbicidal products contained within granules. The ability of PMNs to remove and kill bacteria is essential towards maintenance of human health. Although the majority of microorganisms are readily killed by PMNs, several important bacterial pathogens are able to subvert the human innate immune response to cause disease. Yersinia pestis, the causative agent of plague and one of the most virulent and notorious of all pathogens, is able to evade the innate immune response and flourish in lymphoid tissue. However, the molecular mechanisms used by this important human pathogen to alter PMN function are not well characterized. The broad goal of this study is to identify key molecular processes involved in the human polymorphonuclear leukocyte response to Yersinia pestis that underlie bacterial pathogenesis. Based on our preliminary findings, we propose to address in depth, the role of the neutrophil in the human innate immune response against Y. pestis. This will be achieved by studies directed at two specific aims: 1) to investigate the mechanisms used by Y. pestis to evade phagocytosis and killing by human PMNs; and 2) to characterize post-phagocytosis sequelae in human neutrophils exposed to Y. pestis. We anticipate that these studies will provide important insight into Y. pestis pathogenesis. However, the most significant aspect of the proposed research is the potential for a better understanding of the role for the human innate immune system in defense against plague. [unreadable] [unreadable] [unreadable]